Insoluble pharmacologically active agents, e.g., itraconazole, progesterone, cyclosporin, carbamazepine, fenofibrate, amphotericin B, naproxen, and glyburide, present oral absorption challenges due to their low solubility in aqueous medium. According to the Noyes-Whitney equation (Alfred Martin et al., Physical Pharmacy, 3rd ed, page 575), drug dissolution rate is directly proportional to its solubility, and hence an insoluble drug is intrinsically of slow dissolution. Many insoluble pharmacologically active agents are present in crystalline form that can be an additional energy barrier to drug dissolution.
As the pharmacologically active agent (e.g., drug) moves through the human gastrointestinal tract after oral administration, its typical residence time in the stomach, intestines and colon is about 30 minutes, 3 hours and 30 hours, respectively. The pharmacologically active agent must dissolve in these time windows to allow for absorption. A pharmacologically active agent with a slow rate of dissolution, i.e., a significant portion of the agent fails to dissolve during its transit through the gastrointestinal tract, will simply not be entirely absorbed.
It is well understood that slow dissolution is a major reason for lack of oral absorption of insoluble pharmacologically active agents, and can cause an otherwise promising drug candidate compound to fail further drug development. Slow dissolution is also frequently related to high absorption variability among patients, high food effect on absorption and lack of dose-exposure relationship. Each of these can contribute to suboptimal drug performance. It is estimated that 40-60% of discovered drug substances are insoluble and many of them suffer from the oral absorption problem.
Several approaches have been developed to improve solubility and/or dissolution rate of insoluble pharmacologically active agents. Common approaches include: converting an insoluble pharmacologically active agent into a more soluble salt or crystalline form including amorphous form; reducing the particle size of an insoluble pharmacologically active agent for faster dissolution; dissolving an insoluble pharmacologically active agent in a liquid medium comprising water-soluble components such as solvents and surfactants, etc., to form a “liquid formulation” (such as, for example, an emulsion); and dissolving or dispersing an insoluble pharmacologically active agent in a solid matrix comprising water-soluble or hydrophilic components, such as a solid polymer or lipids, to form a “solid dispersion formulation”.
The above approaches have been applied in preparing or formulating some successful drug products. Insoluble naproxen was made soluble by forming a sodium salt, which is the active ingredient of the drug Naprosyn®. Size reduction by micronization has lead to drugs Prometrium® (micronized progesterone) and Micronase® (micronized glyburide). Dissolving the drug in a water-soluble liquid composition was the basis for drugs such as Sandimmune® (cyclosporin emulsion) and Neoral® (cyclosporin microemulsion). Dispersion of the insoluble griseofulvin in a solid dispersion matrix comprising water-soluble polymer propylene glycol (PEG) resulted in the drug Gris-PEG®.
The above approaches are based on the physical chemistry theories of drug solubility and dissolution. For example, a salt or an amorphous form of a pharmacologically active agent is commonly known to be more soluble and of faster dissolution than the unmodified pharmacologically active agent itself. Particle size reduction generates a greater surface area and a greater surface area leads to a faster dissolution rate as predicted by the Noyes-Whitney equation (Alfred Martin et al, Physical Pharmacy, 3rd ed, page 575). The liquid formulation first breaks up the crystals of the pharmacologically active agent by dissolving it in a water-soluble solvent and such water-liking solution can then readily be mixed into another aqueous environment such as gastric fluid, carrying the dissolved pharmacologically active agent to achieve a fast dissolution. Similarly, in a solid dispersion formulation, the insoluble pharmacologically active agent is also first dissolved or dispersed in a solid matrix formed with a soluble ingredient, e.g. PEG or PVP, the matrix can then be readily mixed into the aqueous biological milieu providing a fast dissolution of the dissolved pharmacologically active agent, owing to the hydrophilic nature of the matrix-forming ingredient.
In essence, the liquid formulation and solid dispersion formulation are based on the same principle, i.e., (1) to dissolve the insoluble pharmacologically active agent in a water-soluble or hydrophilic matrix (liquid or solid) first to break the crystalline structure of the pharmacologically active agent, and (2) to render a fast mixing of the water-liking matrix with a biological aqueous milieu (gastric or intestinal fluid) with the already dissolved or dispersed pharmacologically active agent in it to allow for a fast dissolution.
In practice, these approaches suffer from several disadvantages. Some insoluble pharmacologically active agents cannot be converted to the more soluble salts or crystalline form, especially those that lack ionizable groups. Particle size reduction by micronization or nanonization presents processing and stability challenges, as well as dissolution limitations, since the micronized or nanosized pharmacologically active agent may still possess a high degree of crystallinity. Liquid formulations present drug precipitation and packaging challenges, due to solvent evaporation. Moreover, non-solid formulations are more prone to chemical instability and capsule-shell incompatibility, leading to the possibility of leakage upon storage. Solid dispersion formulations often suffer from re-crystallization of the insoluble pharmacologically active agent over time, resulting in decreased dissolution.